Mitotic spindle poisons

Mechanism of action

Mitotic spindle poisons or anti-microtubule agents are important drugs for cancer therapy. Two drug classes will be discussed here: vinca alkaloids and taxanes. Microtubules are protein polymers that assist in cell movement and maintain cell shape/integrity. They regularly assemble and disassemble as required throughout the cell cycle. They are essential for cell division, to correctly separate the duplicated set of chromosomes and ensure each daughter cell gets the appropriate number of chromosomes during division. When the dissasembly/assembly of microtubules is disrupted, as happens with these drugs, cancer cell death can ensue. Anti-microtubule drugs are M phase specific, meaning they have their physiologic effect when the cancer cell enters the M phase of the cell cycle and mitosis occurs. Vinca alkaloids (vincristine) and taxanes (paclitaxel) both target the microtubule, but they have opposite mechanisms of action concerning where and when they bind. Vinca alkaloids bind to the tubulin subunits of the microtubule and prevent assembly of the microtubule complex. In contrast, taxanes bind to the microtubule itself, and prevent disassembly into constituent subcomponents.  

Administration, side-effects and mitigation strategies

Vinca alkaloids are potent vesicants, and when the patient is receiving the infusion apply warm packs (heat pads) and administer hyaluronidase to reduce the possible inflammation. Vinblastine is associated with a dose-limiting toxicity of thrombocytopenia. Additional toxicities include neurologic toxicities, constipation, and abdominal cramps. Vincristine has similar side effects. It is the most potent of the vinca analogs and can interfere with axonal transport (which rely on microtubules). These drugs are used for leukemias, lymphomas, and solid tumors. They are common in many regimens, despite their side effects and dangers. These drugs are fatal if administered intrathecally (in the spinal cord).  

Taxanes prevent the disassembly of microtubules. Paclitaxel is used in solid tumors and is associated with dose-limiting toxicity. Since they can be combined with other drugs, taxanes are usually prescribed before platinum analogs which seems to minimize the myelosuppression that can occur. Peripheral neuropathy, motor deficits, and myopathic effects are common. Hypersensitivity reactions can occur as well, usually during the first dose (almost half of the patients experience a reaction with the first dose). Reactions show a diffuse and intense erythroderma, tachycardia, pruritus, and chest tightness. To alleviate/combat this inevitable response, patients are premedicated with dexamethasone and diphenhydramine. The infusion may be stopped momentarily, and resumed after 30 mins. Infusions are stopped when respiratory compromise is evident, at which point the patient must switch to a new regimen without the taxane. Along the lines of preventing toxicity, the drug can be combined with nanoparticles to allow for increased concentration into the tumor without some of the capillary adverse effects. Common side effects to paclitaxel include a dose-limiting leukopenia, hypersensitivity reactions (already discussed), alopecia, cardiac toxicity, peripheral neuropathies, and mucositis. Docetaxel side effects include a more potent leukopenia, peripheral edema, peripheral neuropathies, and hypersensitivity reaction.